Submissions for variant NM_152564.5(VPS13B):c.9551A>G (p.Glu3184Gly)

gnomAD frequency: 0.00001  dbSNP: rs772361332

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179110	SCV000231306	uncertain significance	not provided	2014-12-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242081	SCV001415145	uncertain significance	Cohen syndrome	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 3209 of the VPS13B protein (p.Glu3209Gly). This variant is present in population databases (rs772361332, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 197938). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VPS13B protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000179110	SCV001993819	uncertain significance	not provided	2019-05-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001818441	SCV002067995	uncertain significance	not specified	2020-04-30	criteria provided, single submitter	clinical testing	DNA sequence analysis of the VPS13B gene demonstrated a sequence change, c.9626A>G, in exon 52 that results in an amino acid change, p.Glu3209Gly. This sequence change has been described in the EXAC database with a low population frequency of 0.001592 (dbSNP rs772361332). The p.Glu3209Gly change affects a moderately conserved amino acid residue located in a domain of the VPS13B protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu3209Gly substitution. This sequence change does not appear to have been previously described in patients with VPS13B-related disorders. Due to these contrasting evidences and the lack of sufficient data, the clinical significance of the p.Glu3209Gly change remains unknown at this time.
Ambry Genetics	RCV002381578	SCV002693828	uncertain significance	Inborn genetic diseases	2018-01-12	criteria provided, single submitter	clinical testing	The p.E3209G variant (also known as c.9626A>G), located in coding exon 51 of the VPS13B gene, results from an A to G substitution at nucleotide position 9626. The glutamic acid at codon 3209 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics	RCV000179110	SCV005196065	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV001242081	SCV002082716	uncertain significance	Cohen syndrome	2019-11-11	no assertion criteria provided	clinical testing